Subclonal diversification of primary breast cancer revealed by multiregion sequencing
Abstract
Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.
- Authors:
-
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- Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Cambridge, Cambridge (United Kingdom)
- Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
- Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
- Univ. Libre de Bruxelles, Brussels (Belgium)
- Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Leuven, Leuven (Belgium)
- Haukeland Univ. Hospital, Bergen (Norway)
- Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Haukeland Univ. Hospital, Bergen (Norway); Univ. of Bergen, Bergen (Norway)
- Dana-Farber Cancer Institute, Boston, MA (United States)
- Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1236604
- Report Number(s):
- LA-UR-14-28200
Journal ID: ISSN 1078-8956; nm.3886
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- Nature Medicine
- Additional Journal Information:
- Journal Volume: 21; Journal Issue: 7; Journal ID: ISSN 1078-8956
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; breast cancer; cancer genomics; cell migration; evolutionary genetics
Citation Formats
Yates, Lucy R., Gerstung, Moritz, Knappskog, Stian, Desmedt, Christine, Gundem, Gunes, Van Loo, Peter, Aas, Turid, Alexandrov, Ludmil B., Larsimont, Denis, Davies, Helen, Li, Yilong, Ju, Young Seok, Ramakrishna, Manasa, Haugland, Hans Kristian, Lilleng, Peer Kaare, Nik-Zainal, Serena, McLaren, Stuart, Butler, Adam, Martin, Sancha, Glodzik, Dominic, Menzies, Andrew, Raine, Keiran, Hinton, Jonathan, Jones, David, Mudie, Laura J., Jiang, Bing, Vincent, Delphine, Greene-Colozzi, April, Adnet, Pierre -Yves, Fatima, Aquila, Maetens, Marion, Ignatiadis, Michail, Stratton, Michael R., Sotiriou, Christos, Richardson, Andrea L., Lønning, Per Eystein, Wedge, David C., and Campbell, Peter J. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. United States: N. p., 2015.
Web. doi:10.1038/nm.3886.
Yates, Lucy R., Gerstung, Moritz, Knappskog, Stian, Desmedt, Christine, Gundem, Gunes, Van Loo, Peter, Aas, Turid, Alexandrov, Ludmil B., Larsimont, Denis, Davies, Helen, Li, Yilong, Ju, Young Seok, Ramakrishna, Manasa, Haugland, Hans Kristian, Lilleng, Peer Kaare, Nik-Zainal, Serena, McLaren, Stuart, Butler, Adam, Martin, Sancha, Glodzik, Dominic, Menzies, Andrew, Raine, Keiran, Hinton, Jonathan, Jones, David, Mudie, Laura J., Jiang, Bing, Vincent, Delphine, Greene-Colozzi, April, Adnet, Pierre -Yves, Fatima, Aquila, Maetens, Marion, Ignatiadis, Michail, Stratton, Michael R., Sotiriou, Christos, Richardson, Andrea L., Lønning, Per Eystein, Wedge, David C., & Campbell, Peter J. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. United States. https://doi.org/10.1038/nm.3886
Yates, Lucy R., Gerstung, Moritz, Knappskog, Stian, Desmedt, Christine, Gundem, Gunes, Van Loo, Peter, Aas, Turid, Alexandrov, Ludmil B., Larsimont, Denis, Davies, Helen, Li, Yilong, Ju, Young Seok, Ramakrishna, Manasa, Haugland, Hans Kristian, Lilleng, Peer Kaare, Nik-Zainal, Serena, McLaren, Stuart, Butler, Adam, Martin, Sancha, Glodzik, Dominic, Menzies, Andrew, Raine, Keiran, Hinton, Jonathan, Jones, David, Mudie, Laura J., Jiang, Bing, Vincent, Delphine, Greene-Colozzi, April, Adnet, Pierre -Yves, Fatima, Aquila, Maetens, Marion, Ignatiadis, Michail, Stratton, Michael R., Sotiriou, Christos, Richardson, Andrea L., Lønning, Per Eystein, Wedge, David C., and Campbell, Peter J. 2015.
"Subclonal diversification of primary breast cancer revealed by multiregion sequencing". United States. https://doi.org/10.1038/nm.3886. https://www.osti.gov/servlets/purl/1236604.
@article{osti_1236604,
title = {Subclonal diversification of primary breast cancer revealed by multiregion sequencing},
author = {Yates, Lucy R. and Gerstung, Moritz and Knappskog, Stian and Desmedt, Christine and Gundem, Gunes and Van Loo, Peter and Aas, Turid and Alexandrov, Ludmil B. and Larsimont, Denis and Davies, Helen and Li, Yilong and Ju, Young Seok and Ramakrishna, Manasa and Haugland, Hans Kristian and Lilleng, Peer Kaare and Nik-Zainal, Serena and McLaren, Stuart and Butler, Adam and Martin, Sancha and Glodzik, Dominic and Menzies, Andrew and Raine, Keiran and Hinton, Jonathan and Jones, David and Mudie, Laura J. and Jiang, Bing and Vincent, Delphine and Greene-Colozzi, April and Adnet, Pierre -Yves and Fatima, Aquila and Maetens, Marion and Ignatiadis, Michail and Stratton, Michael R. and Sotiriou, Christos and Richardson, Andrea L. and Lønning, Per Eystein and Wedge, David C. and Campbell, Peter J.},
abstractNote = {Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.},
doi = {10.1038/nm.3886},
url = {https://www.osti.gov/biblio/1236604},
journal = {Nature Medicine},
issn = {1078-8956},
number = 7,
volume = 21,
place = {United States},
year = {Mon Jun 22 00:00:00 EDT 2015},
month = {Mon Jun 22 00:00:00 EDT 2015}
}
Web of Science
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